ABSTRACT Every organism requires the ability to detect mechanical stimuli as it is a critical process to discriminate between environmental cues. Despite the fundamental advantages of somatosensation, little is known about the molecular regulation of this process. Recently, Piezo2 channels were discovered as the channels responsible of conducting rapidly-adapting mechanically activated (RA-MA) currents. These channels are highly expressed in primary sensory neurons in vertebrates (Dorsal Root Ganglion (DRG) neurons) and their combined deletion in Merkel cells and DRG neurons abolishes light touch in mice. RA-MA Piezo2 currents are enhanced by inflammatory signals involving a PKC dependent mechanism as well as cAMP dependent mechanism via EPAC; pathways which have been linked to mechanical hyperalgesia, one of the symptoms of chronic pain described as painful responses to innocuous stimuli. However, the mechanisms that regulate this process are still poorly understood. Recent data from our lab shows that activation of Transient Receptor Potential Vanilloids 1 (TRPV1) channels by capsaicin leads to inhibition of RA-MA Piezo2 currents in DRG neurons. This inhibition is abolished by performing similar experiments in Ca2+ free solution, implying an essential role of Ca2+ in the regulation of mechanically activated currents, but how Ca2+ regulates mediates the inhibition of Piezo2 currents is not fully understood. Our preliminary data shows that inhibition of Ca2+/ calmodulin (CaM) activated protein kinases alleviates this inhibition. In addition, we have also found that activation of G-protein coupled receptors (GPCR-s) sensitizes Piezo2 currents. We hypothesize that the Ca2+ influx through TRPV1 channels promotes the activation of Ca2+-dependent intracellular pathways such as Ca2+/ CaM activated kinases thus inhibiting Piezo2 channels while activation of GPCR-s sensitize Piezo2 currents by activation or direct binding of a G-protein. We aim to investigate the role of Ca2+ and GPCR signaling in the regulation of mechanoreceptors and dissect specific molecules and proteins that can potentially serve as a basis for the development of new drug targets for the treatment of mechanical-pain syndromes.